The risk for many common diseases, including some of the leading causes of death in the United States (e.g. cardiovascular disease) is partially due to regulatory genetic variation. This type of variation in human genomes causes differences in gene expression among individuals. Motivated by their important role in disease, thousands of genomic regions harboring regulatory variants have been mapped in human populations, and have revealed key insights about regulatory variation. In spite of this impressive progress, severe gaps in knowledge remain, restricting our ability to link regulatory variation to disease. Although most genes act through their protein products, nearly all work on regulatory variation has used mRNA levels as a measure of gene expression. However, substantial discrepancies between genetic influences on mRNA vs. protein levels have been reported. These discrepancies suggest key gaps in our understanding of how regulatory variation shapes cell biology and disease. Further, global estimates suggest that most regulatory variants act through trans-acting factors that reside far from their target genes, typically on different chromosomes. By contrast, most of the individual genomic regions that have been identified to carry human regulatory variation are located close to their target genes and act in cis. The nature of most trans-acting variants is poorly understood. Finally, current study designs in humans are powered to detect the effects of ?common? variants that are shared by many individuals in the population. The effects of rare variants and especially of ?private? variants that only exist in single individuals remain almost entirely unexplored. This proposal will establish an approach for mapping trans-acting genetic influences on protein levels and other cellular traits in cells derived from human individuals. The method will be developed and applied in two specific aims. The first aim will map genetic variation in proteasome activity, a crucial determinant of protein abundance in a diploid human cell line. The second aim will map trans effects on protein levels in induced pluripotent stem cells. The long-term objective of this proposal is to introduce this mapping technique as a new tool for human genetics. To this end, the proposed work will establish all necessary experimental and computational components of the approach, enabling broad application to research into human biology, disease, and health. Future applications may include comprehensive mapping of trans effects on the human proteome, and could improve strategies for mapping the genetic causes of Mendelian syndromes in individual patients.